NM_000249.4(MLH1):c.1744C>T (p.Leu582Phe) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 2, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000556108.4

Allele description [Variation Report for NM_000249.4(MLH1):c.1744C>T (p.Leu582Phe)]

NM_000249.4(MLH1):c.1744C>T (p.Leu582Phe)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1744C>T (p.Leu582Phe)

HGVS:

NC_000003.12:g.37047531C>T
NG_007109.2:g.59182C>T
NM_000249.4:c.1744C>TMANE SELECT
NM_001167617.3:c.1450C>T
NM_001167618.3:c.1021C>T
NM_001167619.3:c.1021C>T
NM_001258271.2:c.1744C>T
NM_001258273.2:c.1021C>T
NM_001258274.3:c.1021C>T
NM_001354615.2:c.1021C>T
NM_001354616.2:c.1021C>T
NM_001354617.2:c.1021C>T
NM_001354618.2:c.1021C>T
NM_001354619.2:c.1021C>T
NM_001354620.2:c.1450C>T
NM_001354621.2:c.721C>T
NM_001354622.2:c.721C>T
NM_001354623.2:c.721C>T
NM_001354624.2:c.670C>T
NM_001354625.2:c.670C>T
NM_001354626.2:c.670C>T
NM_001354627.2:c.670C>T
NM_001354628.2:c.1744C>T
NM_001354629.2:c.1645C>T
NM_001354630.2:c.1732-986C>T
NP_000240.1:p.Leu582Phe
NP_000240.1:p.Leu582Phe
NP_001161089.1:p.Leu484Phe
NP_001161090.1:p.Leu341Phe
NP_001161091.1:p.Leu341Phe
NP_001245200.1:p.Leu582Phe
NP_001245202.1:p.Leu341Phe
NP_001245203.1:p.Leu341Phe
NP_001341544.1:p.Leu341Phe
NP_001341545.1:p.Leu341Phe
NP_001341546.1:p.Leu341Phe
NP_001341547.1:p.Leu341Phe
NP_001341548.1:p.Leu341Phe
NP_001341549.1:p.Leu484Phe
NP_001341550.1:p.Leu241Phe
NP_001341551.1:p.Leu241Phe
NP_001341552.1:p.Leu241Phe
NP_001341553.1:p.Leu224Phe
NP_001341554.1:p.Leu224Phe
NP_001341555.1:p.Leu224Phe
NP_001341556.1:p.Leu224Phe
NP_001341557.1:p.Leu582Phe
NP_001341558.1:p.Leu549Phe
LRG_216t1:c.1744C>T
LRG_216:g.59182C>T
LRG_216p1:p.Leu582Phe
NC_000003.11:g.37089022C>T
NM_000249.3:c.1744C>T
P40692:p.Leu582Phe

Protein change:

L224F

Links:

UniProtKB: P40692#VAR_076349; dbSNP: rs63751713

NCBI 1000 Genomes Browser:

rs63751713

Molecular consequence:

NM_001354630.2:c.1732-986C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1744C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1450C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1744C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1021C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1450C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1744C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1645C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000625096	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 2, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20020535, 22753075, 18415027, 12547705, 27435373, 30998989, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625096

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 2, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1.

Drost M, Zonneveld Je, van Dijk L, Morreau H, Tops CM, Vasen HF, Wijnen JT, de Wind N.

Hum Mutat. 2010 Mar;31(3):247-53. doi: 10.1002/humu.21180.

PubMed [citation]

PMID:: 20020535

Functional characterization of MLH1 missense variants identified in Lynch syndrome patients.

Andersen SD, Liberti SE, Lützen A, Drost M, Bernstein I, Nilbert M, Dominguez M, Nyström M, Hansen TV, Christoffersen JW, Jäger AC, de Wind N, Nielsen FC, Tørring PM, Rasmussen LJ.

Hum Mutat. 2012 Dec;33(12):1647-55. doi: 10.1002/humu.22153. Epub 2012 Jul 23.

PubMed [citation]

PMID:: 22753075

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000625096.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect MLH1 protein function (PMID: 20020535, 22753075, 30998989). This variant has been observed in individual(s) with Lynch syndrome (PMID: 18415027, 12547705, 27435373, 30998989, Invitae). ClinVar contains an entry for this variant (Variation ID: 89870). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 582 of the MLH1 protein (p.Leu582Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 11, 2024

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